Abstract Tuberculosis (TB) is the leading cause of death in Human Immunodeficiency Virus (HIV)-infected individuals globally. The majority of HIV-negative individuals infected with Mycobacterium tuberculosis (Mtb) are asymptomatic, and are considered to have latent TB infection (LTBI), providing compelling evidence for host immune control of infection. Co-infection with HIV increases the risk of progressing to active TB disease (ATB) by over 20 fold but the underlying immune mechanisms remain unclear. Antiretroviral therapy (ART) decreases the incidence of ATB in HIV-infected individuals and remains the cornerstone of HIV care. However, the incidence of TB in HIV-coinfected individuals remains 4- to 7-fold higher after ART than in HIV-uninfected people in TB-endemic settings, regardless of the duration of ART or attainment of high CD4 counts. Thus, immune control of Mtb infection is not fully restored by ART. Recent clinical trials have shown that regimens that concurrently administer Isoniazid Preventive Treatment (IPT) and ART are significantly better than ART alone in reducing TB incidence among individuals with LTBI. However, uptake of concurrent ART and IPT regimens remains poor and the immune mechanisms underlying the benefits of concurrent ART and IPT have not been defined. We propose to identify the components of TB immunity in the blood and lung compartments that remain impaired after ART, versus those that are restored by concurrent ART and IPT, in the rhesus macaque nonhuman primate (NHP) aerosol model of LTBI and Simian Immunodeficiency Virus (SIV) co-infection. We hypothesize that co-infection with SIV increases Mtb burden within alveolar macrophages in the lung and progressively impairs the functional capacities of tissue-resident Mtb-specific CD4 and CD8 T cells in the lung; ART only partially restores these functions. We further hypothesize that IPT-mediated reduction in Mtb burden, in conjunction with ART, enhances protective Mtb-specific T cell immunity compared to ART alone. We will model these concurrent regimens in a highly faithful model of Mtb/HIV co-infection in rhesus macaques to study the kinetics of lung-specific CD4 and CD8 T cell responses by longitudinal sampling of blood, bronchoalveolar lavage (BAL) and lung biopsy tissue. In Aim 1 we will investigate the role of tissue-resident CD4 T cells in reconstituting Mtb-specific immunity after concurrent ART/IPT regimens versus ART alone. In Aim 2 we will test the hypothesis that SIV-induced progressive impairment of Mtb-specific CD8 functions in lung compartments are better restored by concurrent ART/IPT regimens than by ART alone. By identifying mechanisms underlying restoration of Mtb-specific immune function after concurrent ART and IPT, our studies have the potential to provide new insights into immune pathways that can be targeted for host-directed adjunctive therapies for TB/HIV co-infection and incorporated into designing better vaccines for TB.